Defects in lymphatic vessel growth cause human lymphedema while tumor-induced lymphangiogenesis provides a route for tumor metastasis. At the present time there exist no therapies to either stimulate or suppress lymphatic vessel growth to treat these diseases. Although recent genetic studies have provided new molecular insight into lymphatic vascular development and growth, these studies are small in number and the signaling pathways identified to date are restricted to those that do not disrupt the blood vessel growth that precedes lymphatic vascular development. Gene expression studies reveal that many of the signaling pathways critical for blood vessel growth are also expressed in lymphatic endothelial cells. Notch receptors are expressed in lymphatic endothelial cells and we hypothesize that Notch signaling regulates lymphatic vessel growth and development. There is presently no genetic means of investigating the function of this or other signaling pathways specifically in lymphatic vessels. The goal of this proposal is open genetic investigation of lymphangiogenesis by engineering transgenic mice to drive and delete gene expression exclusively in lymphatic endothelial cells and test the role of Notch signaling in lymphatic vessel growth. PUBLIC HEALTH RELEVANCE: Lymphatic vessels are needed to remove fluid from tissues and edema secondary to lymphatic vascular insufficiency is a common side effect of radiation treatment and infectious diseases. This proposal will develop the genetic tools necessary to investigate the signaling pathways that guide the formation of lymphatic vessels using bi-transgenic mice with which to drive Cre recombinase expression specifically in lymphatic endothelial cells. We will use these mice to address the lymphatic role of Notch signaling, a pathway with multiple necessary roles in blood vessel development and growth. These studies are expected to contribute to the development of new ways to treat of lymphatic vascular diseases.